Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons

The hypocretins (hcrts), also known as orexins, are two recently identified excitatory neuropeptides that in rat are produced by similar to 1200 neuro ns whose cell bodies are located in the lateral hypothalamus. The hypocreti ns/orexins have been implicated in the regulation of rapid eye movement (RE M) sleep and the pathophysiology of narcolepsy. In the present study, we in vestigated whether the locus coeruleus (LC), a structure receiving dense hc rtergic innervation, which is quiescent during REM sleep, might be a target for hcrt to regulate REM sleep. Local administration of hcrt1 but not hcrt 2 in the LC suppressed REM sleep in a dose-dependent manner and increased w akefulness at the expense of deep, slow-wave sleep. These effects were bloc ked with an antibody that neutralizes hcrt binding to hcrt receptor 1. In s itu hybridization and immunocytochemistry showed the presence of hcrt recep tor 1 but not the presence of hcrt receptor 2 in the LC. Iontophoretic appl ication of hcrt1 enhanced the firing rate of LC neurons in vivo, and local injection of hcrt1 into the LC induced the expression of c-fos in the LC ar ea. We propose that hcrt receptor 1 in the LC is a key target for REM sleep regulation and might be involved in the pathophysiological mechanisms of n arcolepsy.